Ethotoin Disease Interactions

Hematologic toxicities have been associated with the use of hydantoin anticonvulsants, particularly mephenytoin. Thrombocytopenia, leukopenia, neutropenia, agranulocytosis, pancytopenia and, rarely, hemolytic anemia, aplastic anemia and pure red cell aplasia have been reported. Therapy with hydantoin anticonvulsants should be administered cautiously in patients with preexisting blood dyscrasias and/or bone marrow depression. Complete blood counts, including platelets, should be performed prior to initiating therapy and regularly for several months thereafter. For mephenytoin, the manufacturer recommends performing counts after 2 weeks on a low dosage, after another 2 weeks when full dosage is reached, then monthly for a year, and every 3 months thereafter. Marked depression of blood counts may be indication for withdrawal of hydantoin therapy.

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Hydantoin anticonvulsants are primarily metabolized by the liver. Both metabolic activity and plasma protein binding may be significantly altered in patients with liver disease, resulting in elevated drug levels (total and unbound fraction) and increased risk of toxicity. Therapy with hydantoin anticonvulsants should be administered cautiously in patients with impaired hepatic function. Reduced dosages and slower titration may be necessary. In addition, periodic monitoring of liver function is recommended, since the use of anticonvulsants, including hydantoins, has been associated with hepatotoxicity related to drug hypersensitivity. Hepatic failure and death have occurred. Hydantoin therapy should be discontinued and not readministered if evidence of liver damage is observed and felt to be drug-related.

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The use of phenytoin has rarely been associated with exacerbation of porphyria. Therapy with phenytoin should be administered cautiously in patients with porphyria. The same precaution should also be observed with other hydantoin anticonvulsants (i.e. ethotoin and mephenytoin) because of their structural and pharmacological similarities to phenytoin.

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Antiepileptic drugs (AEDs) have been associated with an increased risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies involving the use of 11 different AEDs showed that patients receiving AEDs had approximately twice the risk of suicidal thinking or behavior compared to patients receiving placebo. AEDs should be administered cautiously in patients with depression or other psychiatric disorders; phentermine-topiramate should be avoided in patients with history of suicidal attempts or active suicidal ideation. The risk of suicidal thoughts and behavior should be carefully assessed against the risk of untreated illness, bearing in mind that epilepsy and many other conditions for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, caregivers, and families should be alert to the emergence or worsening of signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior. If patients have symptoms of suicidal ideation or behavior, a dosage reduction or treatment discontinuation should be considered.

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Phenytoin, particularly in high dosages, may cause hyperglycemia by inhibiting insulin release. The drug may also raise serum glucose levels in diabetic patients. Therapy with phenytoin should be administered cautiously in patients with diabetes mellitus, glucose intolerance, or a predisposition to hyperglycemia. Patients with diabetes mellitus should be monitored more closely during phenytoin therapy, and their antidiabetic regimen adjusted accordingly. The same precautions should also be observed with other hydantoin anticonvulsants (i.e. ethotoin and mephenytoin) because of their structural and pharmacological similarities to phenytoin.

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Hydantoin anticonvulsants may interfere with folate metabolism and precipitate macrocytosis and megaloblastic anemia, which usually respond to folic acid therapy. These reactions have been fairly uncommon but may be of concern in patients with megaloblastic anemia or folate deficiency receiving hydantoin therapy.

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Phenytoin may interfere with vitamin D metabolism. Hypocalcemia and osteomalacia have been reported. Therapy with phenytoin should be administered cautiously in patients with preexisting vitamin D deficiency. The same precaution should also be observed with other hydantoin anticonvulsants (i.e. ethotoin and mephenytoin) because of their structural and pharmacological similarities to phenytoin.

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